Every year, more than one million deaths are attributed to malaria and approximately 40% of the world's six billion people remain at risk of contracting the disease. Such staggering numbers make the development of an effective control strategy of the highest importance. One proposed methodology for disease intervention capitalizes on the obligate requirement for development of the malaria parasite (Plasmodium) within the mosquito for malaria transmission. Recent studies have demonstrated that a mosquito serine protease inhibitor, serpin 6 (SRPN6), limits parasite success during the invasion of the midgut and salivary gland epithelium. Serpins are conserved components of many organisms and have been implicated in a variety of cellular events including the regulation of the insect immune response. During both invasive stages of parasite development, the expression of SRPN6 is dramatically increased in response to Plasmodium infection, yet the molecular mechanisms that lead to this response remain unknown. In Specific Aim 1, I will identify the protease target of SRPN6 and thus begin to define the mechanism by which SRPN6 impairs parasite development. In Specific Aim 2, I will elucidate the molecular components that lead to the transcriptional activation of the SRPN6 gene. In Specific Aim 3, I will determine the role of a transcription factor (LL3), a known regulator of SRPN6 expression in response to Plasmodium midgut invasion, in the transcriptional regulation of other co-regulated immune genes. Through these experiments I hope to provide novel insights into mosquito immunity in response to parasite invasion that may lead to new molecular targets for disease intervention strategies. PUBLIC HEALTH RELEVANCE: The transmission of malaria requires the mosquito host. By understanding the mechanisms of parasite invasion and subsequent mosquito immune response, novel strategies for malaria intervention can be developed. The characterization of an anti- parasitic pathway involved in mosquito immunity is outlined within this proposal, which may lead to the development of disease intervention strategies to prevent the spread of malaria.